Cao CN, Luo JW, Xu GZ, et al.
Management of nasopharyngeal adenoid cystic carcinoma.
J Oral Maxillofac Surg. 2013; 71(4):e203-9 [PubMed]

PURPOSE: Nasopharyngeal adenoid cystic carcinomas (NACCs) are rare. No clear consensus is available regarding clinical characteristics and management approaches. The aim of this study was to summarize the clinical characteristics and evaluate the management approaches of NACC.
MATERIALS AND METHODS: The experience of 1 institution with this tumor and the outcomes of treatment were examined. The medical records of 36 patients with NACC at 1 institution from 1963 through 2006 were reviewed.
RESULTS: After a median follow-up of 65.8 months (1.8 to 245.2 mo), the 5- and 10-year overall survival, locoregional failure-free survival, and distant metastasis failure-free survival rates were 70.2% and 31.6%, 63.4% and 49.1%, and 65.0% and 59.6%, respectively. No significant differences were found in locoregional failure-free survival, distant metastasis failure-free survival, or overall survival rates between the group that received radiotherapy alone and the group that received combined modality therapy (radiotherapy plus surgery or surgery plus radiotherapy).
CONCLUSIONS: NACC is a malignancy with a generally favorable prognosis. Radiotherapy alone or a combined modality therapy (radiotherapy plus surgery or surgery plus radiotherapy) is effective in the treatment of NACC.

Nguyen NP, Ceizyk M, Vinh-Hung V, et al.
Feasibility of tomotherapy to reduce cochlea radiation dose in patients with locally advanced nasopharyngeal cancer.
Tumori. 2012; 98(6):709-14 [PubMed]

AIMS AND BACKGROUND: To evaluate the effectiveness of tomotherapy-based image-guided radiotherapy (IGRT) on the radiation dose to the cochlea in patients with nasopharyngeal cancer.
METHODS AND STUDY DESIGN: A retrospective review of five patients undergoing concurrent chemoradiation with tomotherapy for locally advanced nasopharyngeal cancer was performed.
RESULTS: The mean dose to the right and left cochlea was 25 Gy and 35.3 Gy respectively, while the dose to the gross tumor ranged from 70 to 75 Gy. All patients had excellent clinical response to the treatment at a median follow-up of five months.
CONCLUSIONS: IGRT for head and neck cancer delivered by tomotherapy can significantly decrease the radiation dose to the cochlea without sacrificing target volume coverage.

Huang CC, Huang TL, Hsu HC, et al.
Long-term effects of neck irradiation on cardiovascular autonomic function: a study in nasopharyngeal carcinoma patients after radiotherapy.
Muscle Nerve. 2013; 47(3):344-50 [PubMed]

INTRODUCTION: Baroreflex failure has been reported as a late sequalum of neck radiotherapy. In this study we investigated cardiovascular autonomic function in patients after neck radiotherapy to determine predictive factors associated with outcome.
METHODS: Eighty-nine patients with nasopharyngeal carcinoma were evaluated ≥6 months after radiotherapy for cardiovascular autonomic function and compared with 48 control subjects. Inflammatory markers and carotid intima-media thickness were also assessed.
RESULTS: Autonomic parameters of heart rate response to deep breathing and Valsalva ratio were significantly lower in the patient group. Cardiovascular autonomic impairment was generally mild with relative sparing of the efferent cardiovagal pathway. By univariate and multivariate analyses, the time after radiotherapy and C-reactive protein level were significantly associated with the degree of cardiovascular autonomic dysfunction.
CONCLUSIONS: Radiation-induced cardiovascular autonomic impairment is a dynamic and progressive process that occurs long after radiotherapy. Chronic inflammation plays a major role in this process.

Wang Z, Liu JQ, Liu Z, et al.
Tumor-derived IL-35 promotes tumor growth by enhancing myeloid cell accumulation and angiogenesis.
J Immunol. 2013; 190(5):2415-23 [PubMed] Article available free on PMC after 01/03/2014

IL-35 is a member of the IL-12 family of cytokines that is comprised of an IL-12 p35 subunit and an IL-12 p40-related protein subunit, EBV-induced gene 3 (EBI3). IL-35 functions through IL-35R and has a potent immune-suppressive activity. Although IL-35 was demonstrated to be produced by regulatory T cells, gene-expression analysis revealed that it is likely to have a wider distribution, including expression in cancer cells. In this study, we demonstrated that IL-35 is produced in human cancer tissues, such as large B cell lymphoma, nasopharyngeal carcinoma, and melanoma. To determine the roles of tumor-derived IL-35 in tumorigenesis and tumor immunity, we generated IL-35-producing plasmacytoma J558 and B16 melanoma cells and observed that the expression of IL-35 in cancer cells does not affect their growth and survival in vitro, but it stimulates tumorigenesis in both immune-competent and Rag1/2-deficient mice. Tumor-derived IL-35 increases CD11b(+)Gr1(+) myeloid cell accumulation in the tumor microenvironment and, thereby, promotes tumor angiogenesis. In immune-competent mice, spontaneous CTL responses to tumors are diminished. IL-35 does not directly inhibit tumor Ag-specific CD8(+) T cell activation, differentiation, and effector functions. However, IL-35-treated cancer cells had increased expression of gp130 and reduced sensitivity to CTL destruction. Thus, our study indicates novel functions for IL-35 in promoting tumor growth via the enhancement of myeloid cell accumulation, tumor angiogenesis, and suppression of tumor immunity.

Wei Y, Zhou T, Lin H, et al.
Significant associations between GSTM1/GSTT1 polymorphisms and nasopharyngeal cancer risk.
Tumour Biol. 2013; 34(2):887-94 [PubMed]

Glutathione S-transferases play a critical role in the detoxification and elimination of electrophilic carcinogens by conjugating them to glutathione. Homozygous deletions of GSTM1 and GSTT1 have been suggested as risk factors for some cancers, including colorectal, pancreatic, and esophageal cancers. Results of previous individual studies published to estimate the associations between GSTM1/GSTT1 polymorphisms and nasopharyngeal cancer (NPC) risk remained controversial. Thus, we carried out a meta-analysis by pooling the odds ratios (ORs) with corresponding 95 % confidence intervals (95 % CIs) of all currently available case-control studies to shed some light on the contradictory finding. A comprehensive search of the PubMed, Embase, Web of Science, and China National Knowledge Infrastructure databases up to October 20, 2012 was performed to identify eligible studies. A total of 15 separate publications involving 2,226 NPC cases and 3,339 controls were finally included into this meta-analysis. The meta-analysis of total studies showed that the null genotypes of GSTM1 and GSTT1 were both significantly associated with increased risk of NPC (for GSTM1: OR = 1.54, 95 % CI 1.28-1.86, P OR < 0.001; for GSTT1: OR = 2.25, 95 % CI 1.50-3.36, P OR < 0.001). Subgroup analysis by ethnicity suggested that carriers of both GSTM1 and GSTT1 null genotypes in Asians were more susceptible to NPC. Additionally, in the subgroup analysis based on the sample size, significant associations of the GSTM1 and GSTT1 polymorphisms with NPC susceptibility were identified among studies both with larger case sample size (number of cases ≥ 100) and smaller case sample size (number of cases <100). Sensitivity analysis confirmed the stability of our results. These results indicate that the GSTM1 and GSTT1 polymorphisms may play crucial roles in the development of NPC, especially in Asians.

Wang WJ, Wu SP, Liu JB, et al.
MYC regulation of CHK1 and CHK2 promotes radioresistance in a stem cell-like population of nasopharyngeal carcinoma cells.
Cancer Res. 2013; 73(3):1219-31 [PubMed]

Radiotherapy is the most successful nonsurgical treatment for nasopharyngeal carcinoma (NPC). Despite this, the prognosis remains poor. Although NPCs initially respond well to a full course of radiation, recurrence is frequent. The cancer stem cell (CSC) hypothesis provides a framework for explaining the discrepancy between the response of NPC to therapy and the poor survival rate. In this study, a stem cell-like subpopulation (PKH26+) was identified in NPC cell lines using a label-retention technique. PKH26+ cells were enriched for clonogenicity, sphere formation, side-population cells, and resistance to radiotherapy. Using genomic approaches, we show that the proto-oncogene c-MYC (MYC) regulates radiotolerance through transcriptional activation of CHK1 (CHEK1) and CHK2 (CHEK2) checkpoint kinases through direct binding to the CHK1 and CHK2 promoters. Overexpression of c-MYC in the PKH26+ subpopulation leads to increased expression of CHK1 and CHK2 and subsequent activation of the DNA-damage-checkpoint response, resulting in radioresistance. Furthermore, loss of CHK1 and CHK2 expression reverses radioresistance in PKH26+ (c-MYC high expression) cells in vitro and in vivo. This study elucidates the role of the c-MYC-CHK1/CHK2 axis in regulating DNA-damage-checkpoint responses and stem cell characteristics in the PKH26+ subpopulation. Furthermore, these data reveal a potential therapeutic application in reversal of radioresistance through inhibition of the c-MYC-CHK1/CHK2 pathway.

Liu Z, Ji MF, Huang QH, et al.
Two Epstein-Barr virus-related serologic antibody tests in nasopharyngeal carcinoma screening: results from the initial phase of a cluster randomized controlled trial in Southern China.
Am J Epidemiol. 2013; 177(3):242-50 [PubMed]

A nasopharyngeal carcinoma (NPC) mass screening trial using a combination of immunoglobulin A antibodies to Epstein-Barr virus capsid antigen and nuclear antigen-1 by enzyme-linked immunosorbent assay in addition to indirect mirror examination in the nasopharynx and/or lymphatic palpation (IMLP) was conducted in southern China. Cantonese aged 30-59 years residing in 2 cities randomly selected by cluster sampling, Sihui and Zhongshan, were invited to participate in this screening from May 2008 through May 2010. Participants were offered fiberoptic endoscopy examination and/or pathologic biopsy if their serologic tests reached our predefined level of high risk or if results from the physical examination indicated possible cancer (i.e., were IMLP positive). A total of 28,688 individuals were voluntarily screened in the initial round. The overall NPC detection rate was 0.14% (41/28,688) with an early diagnosis rate of 68.3% (28/41) during the first year of follow-up. Thirty-eight of 41 cases (92.7%) were detected among the high-risk group, and 7 of 41 cases (17.1%) were detected among the IMLP-positive group. The 2 Epstein-Barr virus serologic tests by enzyme-linked immunosorbent assay could be a feasible alternative for NPC screening in endemic areas. Further follow-up is needed to examine whether screening has an effect on decreasing mortality from NPC in these areas.

Hildesheim A
Invited commentary: Epstein-Barr virus-based screening for the early detection of nasopharyngeal carcinoma: a new frontier.
Am J Epidemiol. 2013; 177(3):251-3 [PubMed] Article available free on PMC after 01/02/2014

Approximately 2 million new cases of cancer are caused by infections each year. For many of these cancers, we have been successful at developing methods for prevention or effective treatment/control. Epstein-Barr virus (EBV), a ubiquitous infection that establishes lifelong latency, was the first infection to be linked to the development of cancers, including nasopharyngeal carcinoma, lymphomas, and gastric cancer. EBV infection is linked to the development of approximately 200,000 new cancers each year, yet there have been no successful efforts to implement EBV-based strategies for the reduction in the burden of EBV-associated cancers. In this issue of the Journal, Liu et al. (Am J Epidemiol. 2013;177(3):242-250) report results from the enrollment phase of a large effort to demonstrate the efficacy of an EBV-based screening strategy to detect nasopharyngeal carcinoma at early stages and hopefully reduce the mortality associated with this disease. In this invited commentary, the design and initial findings from this demonstration project are reviewed, possible ways to enrich the effort are discussed, and populations that might benefit from EBV-based screening in the future are identified.

Jiang GM, Wang HS, Zhang F, et al.
Histone deacetylase inhibitor induction of epithelial-mesenchymal transitions via up-regulation of Snail facilitates cancer progression.
Biochim Biophys Acta. 2013; 1833(3):663-71 [PubMed]

Histone deacetylase inhibitors (HDACIs) are now emerging as a new class of anticancer drugs. Some of them have been used in clinical treatment for tumors, most impressively in the hematological tumors. But their single-agent activities in epithelial-derived tumors are limited. The mechanisms of these actions of HDACIs are not yet well understood. In this study, it was found for the first time that HDACIs were able to induce epithelial-mesenchymal transitions (EMT) which is believed to trigger tumor cell invasion and metastasis. We show that HDACIs induce fibroblast-like morphology, up-regulate Snail and Vimentin and down-regulate E-cadherin in epithelial cell-derived tumor cell lines. It demonstrates that HDACI treatment enhances further Snail acetylation and reduces its ubiquitylation, and induces Snail transcription as well as Snail nuclear translocation in CNE2 cells. Snail knockdown by siRNAs prevents the change in cell morphology and Vimentin up-regulation in response to HDACIs. The results suggested that Snail plays an important role in the HDACI-induced EMT. It is very crucial for a better understanding of clinical therapeutical failure of HDACIs in the patients with epithelial cell-derived cancers. Therefore, our results indicate that more attention should be paid to the cancer treatment using HDACIs due to the fact that it will enhance the spread risks of cancer cells to facilitate cancer progression and it is very important to select appropriate drugs for different tumors.

Akbas T, Ugurluer G, Arpaci T
Solitary sternal metastasis of nasopharyngeal carcinoma: a case report.
Eur Rev Med Pharmacol Sci. 2012; 16(14):1947-50 [PubMed]

Solitary sternal metastasis of nasopharyngeal carcinoma (NPC) is rare. At the time of diagnosis, distant metastases are found in about 5 to 7% of NPC patients. We report a case of isolated sternal metastasis of nasopharyngeal carcinoma in a 23 year-old man.

Kitagawa N, Kondo S, Wakisaka N, et al.
Expression of seven-in-absentia homologue 1 and hypoxia-inducible factor 1 alpha: novel prognostic factors of nasopharyngeal carcinoma.
Cancer Lett. 2013; 331(1):52-7 [PubMed]

Nasopharyngeal carcinoma (NPC) is an EBV-associated cancer. We analysed Siah1 expression as well as LMP1 and HIF1α expression by immuno-histochemical staining in 74 NPC biopsy specimens and found that the expression of Siah1 was significantly correlated with advanced tumour status and stage. Moreover, Siah1-positive and HIF1α-positive cases had significantly worse prognoses. The expression score for LMP1 was remarkably correlated with that of Siah1, whereas there was little correlation between LMP1 expression and the other markers evaluated. This is the first study to evaluate the pattern and clinical significance of Siah1 and HIF1α expression in NPC, and such an evaluation is valuable for identifying those patients at a high risk for a poor prognosis.

Ho Y, Tsao SW, Zeng M, Lui VW
STAT3 as a therapeutic target for Epstein-Barr virus (EBV): associated nasopharyngeal carcinoma.
Cancer Lett. 2013; 330(2):141-9 [PubMed]

Nasopharyngeal carcinoma (NPC), an endemic head and neck cancer found in Southeast Asia, is etiologically associated with the infection of an oncogenic virus, the Epstein-Barr virus (EBV). Here, we review literature findings on the potential/putative role of STAT3 signaling in its pathogenesis and discuss anti-STAT3 targeting as a therapeutic and possibly prevention strategy for NPC. Lastly, the potential involvement of STAT3 in other oncovirus-associated (e.g. the human papillomavirus) head and neck cancers have not been investigated and we hope that findings in EBV-associated NPC can prompt future investigations in these cancers, which are of increasing impact in the Western countries.

Wu A, Luo W, Zhang Q, et al.
Aldehyde dehydrogenase 1, a functional marker for identifying cancer stem cells in human nasopharyngeal carcinoma.
Cancer Lett. 2013; 330(2):181-9 [PubMed]

Aldehyde dehydrogenase 1 (ALDH1) activity has now been employed successfully as a cancer stem cells (CSCs) marker in various tumors. We wanted to investigate whether ALDH1 can be used as a putative CSCs marker and a powerful prognostic factor in nasopharyngeal carcinoma (NPC). Here, we isolated ALDH1-positive cells from human NPC cell lines (5-8F and CNE2) and found that ALDH1-positive cancer cells grew faster and had higher clone formation efficiency (0.435±0.15; 0.431±0.025 vs. 0.131±0.007; 0.121±0.126), differentiation capability and had higher migration (233.00±5.29; 228.60±9.34 vs. 123.20±7.70 vs. 97.20±6.61) than those of ALDH1-negative cancer cells in vitro. In addition, ALDH1- positive cancer cells formed significantly more tumor spheres. Our in vivo experiments showed that only 5×10(3) ALDH1-positive NPC cells were required to induce tumors. Notably, ALDH1-positive cells are enriched in the side-population (SP) cells, and stem cells-like genes OCT4, BMI1, KLF4 and SOX2 are preferentially expressed in ALDH1-positive cells. Immunohistochemical results showed that the expression of ALDH1 correlated significantly with T classification (P=0.011), N classification (P=0.005), M classification (P=0.002) and clinical stage (P=0.001). Interestingly, ALDH1 expression in the tumor correlated significantly with epithelial-mesenchymal transition (EMT) markers including vimentin expression and loss of E-cadherin (P=0.003 and 0.008, respectively). Furthermore, multivariate analyses showed that ALDH1 expression was an independent prognostic indicator (P=0.032). Taken together, for the first time, we demonstrate that ALDH1 could be a novel stem cells marker and a valuable predictor of poor survival NPC.

Liu J, Zhan X, Li M, et al.
Mitochondrial proteomics of nasopharyngeal carcinoma metastasis.
BMC Med Genomics. 2012; 5:62 [PubMed] Article available free on PMC after 01/02/2014

BACKGROUND: Mitochondrial proteomic alterations of nasopharyngeal carcinoma metastasis remain unknown. Our purpose is to screen mitochondrial proteins for the elucidation of the molecular mechanisms of nasopharyngeal carcinoma metastasis and the discovery of metastasis-related biomarkers.
METHODS: Mitochondria were isolated from nasopharyngeal carcinoma metastatic (5-8F) and nonmetastatic (6-10B) cell lines, respectively. After characterization of isolated mitochondria, mitochondrial differentially expressed proteins (DEPs) were quantified by two-dimensional difference in-gel electrophoresis (2D-DIGE), and identified by peptide mass fingerprint (PMF) and tandem mass spectrometry (MS/MS). A functional enrichment analysis and a protein-protein interaction sub-network analysis for DEPs were carried out with bioinformatics. Furthermore, siRNAs transient transfections were used to suppress expressions of some up-regulated DEPs in metastatic cells (5-8F), followed by Transwell Migration assay.
RESULTS: Sixteen mitochondrial DEPs including PRDX3 and SOD2 were identified. Those 5-8F cells with suppression of PRDX3 showed an increased mobility potential. The functional enrichment analyses of DEPs discovered five significant biological processes including cellular response to reactive oxygen species, hydrogen peroxide metabolic process, regulation of mitochondrial membrane potential, cell redox homeostasis and oxidation reduction, and five significant molecular functions including oxidoreductase activity, caspase inhibitor activity, peroxiredoxin activity, porin activity and antioxidant activity. A protein-protein interaction sub-network of DEPs was generated with literature data. Ten mitochondrial DEPs including PRDX3, PRDX6, SOD2, ECH1, SERPINB5, COX5A, PDIA5, EIF5A, IDH3B, and PSMC4 were rationalized in the tumor-stroma co-evolution model that mitochondrial oxidative stress directly contributes to tumor metastasis.
CONCLUSIONS: Sixteen mitochondrial DEPs were identified with mass spectrometry and ten of them were rationalized in the tumor-stroma co-evolution model. Those 5-8F cells with suppression of PRDX3 showed an increased mobility potential. These data suggest that those mitochondrial DEPs are potential biomarkers for NPC metastasis, and their dysregulation would play important roles in mitochondria oxidative stress-mediated NPC metastatic process.

Tang M, Lautenberger JA, Gao X, et al.
The principal genetic determinants for nasopharyngeal carcinoma in China involve the HLA class I antigen recognition groove.
PLoS Genet. 2012; 8(11):e1003103 [PubMed] Article available free on PMC after 01/02/2014

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy facilitated by Epstein-Barr Virus infection. Here we resolve the major genetic influences for NPC incidence using a genome-wide association study (GWAS), independent cohort replication, and high-resolution molecular HLA class I gene typing including 4,055 study participants from the Guangxi Zhuang Autonomous Region and Guangdong province of southern China. We detect and replicate strong association signals involving SNPs, HLA alleles, and amino acid (aa) variants across the major histocompatibility complex-HLA-A, HLA -B, and HLA -C class I genes (P(HLA-A-aa-site-62) = 7.4 × 10(-29); P (HLA-B-aa-site-116) = 6.5 × 10(-19); P (HLA-C-aa-site-156) = 6.8 × 10(-8) respectively). Over 250 NPC-HLA associated variants within HLA were analyzed in concert to resolve separate and largely independent HLA-A, -B, and -C gene influences. Multivariate logistical regression analysis collapsed significant associations in adjacent genes spanning 500 kb (OR2H1, GABBR1, HLA-F, and HCG9) as proxies for peptide binding motifs carried by HLA- A*11:01. A similar analysis resolved an independent association signal driven by HLA-B*13:01, B*38:02, and B*55:02 alleles together. NPC resistance alleles carrying the strongly associated amino acid variants implicate specific class I peptide recognition motifs in HLA-A and -B peptide binding groove as conferring strong genetic influence on the development of NPC in China.

Kao YC, Lee SW, Lin LC, et al.
Fatty acid synthase overexpression confers an independent prognosticator and associates with radiation resistance in nasopharyngeal carcinoma.
Tumour Biol. 2013; 34(2):759-68 [PubMed]

Fatty acid synthase (FASN) is overexpressed in many human cancers and associated with poor prognosis. However, the role of FASN in nasopharyngeal carcinoma (NPC) has not been studied. We evaluated the expression of FASN immunohistochemically in 124 NPC specimens, stratified them into two groups (FASN-high and FASN-low), and examined the correlation with various clinicopathological parameters. In two NPC cell lines, HONE1 and TW01, we targeted the FASN transcript by shRNAi and evaluated the effect on cell proliferation by WST-1 assay and radiation-induced apoptosis by measuring caspase-3 and caspase-7 activation. NPC with high FASN immunoexpression was correlated with advanced pT disease status and worse prognosis in terms of disease-specific survival, metastasis-free survival and local recurrence-free survival, compared to FASN-low group in both univariate and multivariate analyses. In the two NPC cell lines, endogenous FASN expression was significantly higher than the non-tumor keratinocyte, DOK. When the expression of FASN was suppressed by shRNAi, the tumor cells showed decreased cell proliferation and increased apoptosis after radiation. Our results supported FASN as an adverse prognostic marker in NPC, possibly by conferring cell growth advantage and resistance to radiation-induced apoptosis on tumor cells. The inhibition of FASN expression might be investigated as an adjunct in treatment, especially in radiation resistant NPC.

Indrasari SR, Timmermans AJ, Wildeman MA, et al.
Remarkable response to photodynamic therapy in residual T4N0M0 nasopharyngeal carcinoma: a case report.
Photodiagnosis Photodyn Ther. 2012; 9(4):319-20 [PubMed]

Local treatment of residual or recurrent nasopharyngeal carcinoma (NPC) is a challenge. Photodynamic therapy (PDT) is an established treatment modality for incurable head and neck carcinoma. Several studies reported induction of an immune response after PDT. We present a patient with residual T4N0M0 NPC who was treated with PDT for residual disease after initial treatment with neo-adjuvant chemotherapy and radiotherapy. Five years after PDT, the tumor did not progress and the patient is still in good condition. We discuss this remarkable long-term response to PDT and speculate on possible mechanisms.

Glastonbury CM, Salzman KL
Pitfalls in the staging of cancer of nasopharyngeal carcinoma.
Neuroimaging Clin N Am. 2013; 23(1):9-25 [PubMed]

Although nasopharyngeal carcinoma (NPC) is the most common primary malignancy of the nasopharynx, it is an uncommon malignancy in much of the Western world. Over the last several years, there have been important changes in the terminology used for histologic classification of NPC and important changes to the American Joint Committee on Cancer TNM staging of NPC. Accurate imaging assessment is critical for diagnose, to stage and plan radiation treatment, and for ongoing follow-up and surveillance. This article emphasizes important nasopharyngeal anatomy landmarks and the imaging appearances and pitfalls of NPC, its patterns of spread, and posttreatment appearances.

Jagdis A, Phan T, Klimowicz AC, et al.
Assessment of ERCC1 and XPF protein expression using quantitative immunohistochemistry in nasopharyngeal carcinoma patients undergoing curative intent treatment.
Int J Radiat Oncol Biol Phys. 2013; 85(5):1340-5 [PubMed]

PURPOSE: We sought to evaluate the prognostic/predictive value of ERCC1 and XPF in patients with nonmetastatic nasopharyngeal carcinoma (NPC) treated with curative intent.
METHODS AND MATERIALS: ERCC1 and XPF protein expression was evaluated by immunofluorescence combined with automated quantitative analysis (AQUA) using the FL297 and 3F2 antibodies, respectively. ERCC1 and XPF protein expression levels were correlated with clinical outcomes.
RESULTS: Patient characteristics were as follows: mean age 52 years (range, 18-85 years), 67% male, 72% Karnofsky performance status (KPS) ≥ 90%, World Health Organization (WHO) type 1/2/3 = 12%/28%/60%, stage III/IV 65%. With a median follow-up time of 50 months (range, 2.9 to 120 months), the 5-year overall survival (OS) was 70.8%. Median standardized nuclear AQUA scores were used as cutpoints for ERCC1 (n=138) and XPF (n=130) protein expression. Agreement between dichotomized ERCC1 and XPF scores was high at 79.4% (kappa = 0.587, P<.001). Neither biomarker predicted locoregional recurrence, DFS, or OS after adjustment for age and KPS, irrespective of stratification by stage, WHO type, or treatment.
CONCLUSIONS: Neither ERCC1 nor XPF, analyzed by quantitative immunohistochemistry using the FL297 and 3F2 antibodies, was prognostic or predictive in this cohort of NPC patients.

Kan MW, Wong W, Leung LH, et al.
A comprehensive dosimetric evaluation of using RapidArc volumetric-modulated arc therapy for the treatment of early-stage nasopharyngeal carcinoma.
J Appl Clin Med Phys. 2012; 13(6):3887 [PubMed]

The purpose of this study was to investigate the potential benefits of using triple-arc volumetric-intensity modulated arc radiotherapy (RapidArc (RA)) for the treatment of early-stage nasopharyngeal carcinoma (NPC). A comprehensive evaluation was performed including plan quality, integral doses, and peripheral doses. Twenty cases of stage I or II NPC were selected for this study. Nine-field sliding window IMRT, double-arc, and triple-arc RA treatment plans were compared with respect to target coverage, dose conformity, critical organ sparing, and integral doses. Measurement of peripheral doses was performed using thermoluminescent dosimeters in an anthropomorphic phantom. While similar conformity and target coverage were achieved by the three types of plans, triple-arc RA produced better sparing of parotid glands and spinal cord than double-arc RA or IMRT. Double-arc RA plans produced slightly inferior parotid sparing and dose homogeneity than the other two delivery methods. The monitor units (MU) required for triple-arc were about 50% less than those of IMRT plans, while there was no significant difference in the required MUs between triple-arc and double-arc RA plans. The peripheral dose in triple-arc RA was found to be 50% less compared to IMRT near abdominal and pelvic region. Triple-arc RA improves both the plan quality and treatment efficiency compared with IMRT for the treatment of early stage NPC. It has become the preferred choice of treatment delivery method for early stage NPC at our center.

Zhang Z, Sun D, Hutajulu SH, et al.
Development of a non-invasive method, multiplex methylation specific PCR (MMSP), for early diagnosis of nasopharyngeal carcinoma.
PLoS One. 2012; 7(11):e45908 [PubMed] Article available free on PMC after 01/02/2014

Increasing evidence demonstrated that inactivation of tumor suppressor genes (TSGs) by aberrant promoter methylation is an early event during carcinogenesis. Aiming at developing early diagnostic or prognostic tools for various tumors, we took an EBV-associated tumor, nasopharyngeal carcinoma (NPC), as a model and developed a powerful assay based on "multiplex methylation specific-PCR (MMSP)". The MMSP assay was designed to detect tumor-specific methylation status of several NPC-related genes and was capable of acquiring multiplex information simultaneously through a single PCR reaction with the tiny tumor DNA derived from the direct body fluid close to the primary tumor. In this study, we collected paired nasopharyngeal (NP) swabs and NPC biopsies from 49 NPC patients and twenty noncancerous controls. A panel of markers including two EBV, and two cellular TSG markers were applied in this NPC-specific-MMSP assay. We optimized the working condition of MMSP so that it provides information equal to that from the corresponding separate PCRs. The results showed that MMSP patterns of NPC swab were largely consistent with those of corresponding biopsies and significantly distinguished themselves from those of 20 noncancerous volunteers. Among the 69 samples (49 NPCs and 20 normal controls), the sensitivity of detecting NPC from NP swabs is 98%. The specificity is as high as 100%. In conclusion, being characterized by its noninvasiveness, high reproducibility and informativeness, MMSP assay is a reliable and potential diagnostic tool for NPC. It paves the way for the development of population screening and early diagnosis approaches for various tumor types.

Chen C, Wang FH, An X, et al.
Triplet combination with paclitaxel, cisplatin and 5-FU is effective in metastatic and/or recurrent nasopharyngeal carcinoma.
Cancer Chemother Pharmacol. 2013; 71(2):371-8 [PubMed]

PURPOSE: Platinum-based chemotherapy is the recognized first-line treatment for metastatic nasopharyngeal carcinoma (NPC). However, no standard treatment regimens have been established. This phase II study was designed to evaluate the efficacy and safety of a paclitaxel, cisplatin and 5-FU combination in metastatic and/or recurrent NPC.
METHODS: Patients with evaluable metastatic and/or recurrent NPC were entered into this study. Treatment consisted of paclitaxel at a dose of 135 mg/m(2) on day 1, cisplatin 25 mg/m(2)/day from day 1 to day 3 and 5-FU-continuous infusion for 120 h at a variable dosage from 600 to 1,000 mg/m(2)/day according to prior radiation. This regimen was repeated every 3 weeks.
RESULTS: A total of 95 patients were enrolled; 92 patients were evaluable for response. The overall response and disease control rates were 78.9 and 93.6 %, respectively. At a median follow-up of 24.8 months, the respective median overall survival (OS) and progression-free survival were 22.7 months (95 % CI 18.6-26.9 months) and 8.6 months (95 % CI 7.7-9.5 months). Toxicities were moderate and manageable. Grade 3/4 toxicities included leucopenia (14.7 %), neutropenia (17.9 %), anemia (3.2 %), thrombocytopenia (6.4 %), nausea (4.2 %), vomiting (9.5 %), stomatitis (9.5 %), diarrhea (3.2 %), aminotransferase (2.2 %) and sensory neuropathy (3.2 %).
CONCLUSION: Triplet combination chemotherapy with paclitaxel, cisplatin and 5-FU is an effective and safe option in the front-line treatment for recurrent and/or metastatic NPC. The encouraging results with high response rate and long OS suggest that this regimen might be especially considered where tumor shrinkage is required.

Zhang JX, Qian D, Wang FW, et al.
MicroRNA-29c enhances the sensitivities of human nasopharyngeal carcinoma to cisplatin-based chemotherapy and radiotherapy.
Cancer Lett. 2013; 329(1):91-8 [PubMed]

This study was aimed to investigate the potential role of microRNA-29c (miR-29c) in regulating the sensitivities of nasopharyngeal carcinoma (NPC) to ionizing radiation (IR) and cisplatin. Low expression of miR-29c was positively associated with therapeutic resistance in 159 NPC cases. Our further in vitro and in vivo studies illustrated ectopic restoration of miR-29c substantially enhanced the sensitivity of NPC cells to IR and cisplatin treatment by promoting apoptosis. Furthermore, we detected miR-29c repressed expression of anti-apoptotic factors, Mcl-1 and Bcl-2 in NPC tissues and cell lines. These data indicate miR-29c might serve as a potential therapeutic sensitizer in NPC treatment.

Liu N, Tang LL, Sun Y, et al.
MiR-29c suppresses invasion and metastasis by targeting TIAM1 in nasopharyngeal carcinoma.
Cancer Lett. 2013; 329(2):181-8 [PubMed]

Based on microarray analysis, we previously reported that miR-29c is significantly downregulated in nasopharyngeal carcinoma (NPC). However, little is known about the effect and molecular mechanisms of action of miR-29c deregulation during the development and progression of NPC. Quantitative RT-PCR demonstrated that miR-29c was significantly downregulated in NPC cell lines and clinical specimens. Wound healing, Transwell migration and lung metastasis assays demonstrated that ectopic expression of miR-29c inhibited NPC cell migration and invasion in vitro and suppressed the formation of lung metastases in vivo. T cell lymphoma invasion and metastasis 1 (TIAM1) was confirmed as a miR-29c target gene using luciferase reporter assays, quantitative RT-PCR and Western blotting. Ectopic expression of TIAM1 significantly promoted the migration and invasion of SUNE-1 cell line stably overexpressing miR-29c. The prognostic value of TIAM1 was analyzed in 217 NPC patients using immunohistochemistry. Strikingly, patients with high TIAM1 expression had poorer overall, disease-free and distant metastasis-free survival than patients with low TIAM1 expression. Furthermore, multivariate Cox regression analysis revealed that TIAM1 could serve as an independent prognostic factor in NPC. The newly identified miR-29c/TIAM1 pathway further elucidates the molecular mechanisms regulating invasion and metastasis in NPC, and may provide novel prognostic and treatment strategies for NPC patients.

Qi ZY, Deng XW, Cao XP, et al.
A real-time in vivo dosimetric verification method for high-dose rate intracavitary brachytherapy of nasopharyngeal carcinoma.
Med Phys. 2012; 39(11):6757-63 [PubMed]

PURPOSE: A real-time in vivo dosimetric verification method using metal-oxide-semiconductor field effect transistor (MOSFET) dosimeters has been developed for patient dosimetry in high-dose rate (HDR) intracavitary brachytherapy of nasopharyngeal carcinoma (NPC).
METHODS: The necessary calibration and correction factors for MOSFET measurements in (192)Iridium source were determined in a water phantom. With the detector placed inside a custom-made nasopharyngeal applicator, the actual dose delivered to the tumor was measured in vivo and compared to the calculated values using a commercial brachytherapy planning system.
RESULTS: Five MOSFETs were independently calibrated with the HDR source, yielding calibration factors of 0.48 ± 0.007 cGy∕mV. The maximum sensitivity variation was no more than 7% in the clinically relevant distance range of 1-5 cm from the source. A total of 70 in vivo measurements in 11 NPC patients demonstrated good agreement with the treatment planning. The mean differences between the planned and the actually delivered dose within a single treatment fraction were -0.1% ± 3.8% and -0.1% ± 3.7%, respectively, for right and left side assessments. The maximum dose deviation was less than 8.5%.
CONCLUSIONS: In vivo measurement using the real-time MOSFET dosimetry system is possible to evaluate the actual dose to the tumor received by the patient during a treatment fraction and thus can offer another line of security to detect and prevent large errors.

Zhang LY, Ho-Fun Lee V, Wong AM, et al.
MicroRNA-144 promotes cell proliferation, migration and invasion in nasopharyngeal carcinoma through repression of PTEN.
Carcinogenesis. 2013; 34(2):454-63 [PubMed]

Nasopharyngeal carcinoma (NPC) is a type of head and neck cancer with significantly high prevalence in Southern China. Unlike other head and neck cancers, mutations or deletions of tumor suppressor genes in NPC are not common. Recently, downregulation of tumor suppressor genes expression by microRNA (miRNA) is increasingly recognized as an important mechanism of nasopharyngeal tumorigenesis. In this study, we reported that microRNA-144 (miR-144) was frequently upregulated in NPC specimens and cell lines. Repression of miR-144 significantly decreased cell proliferation, clonogenicity, migration, invasion and tumor formation in nude mice, while restoring miR-144 in miR-144-attenuated NPC cells exhibited a strong tumorigenic role. Further, we found that miR-144 was inversely correlated with the tumor suppressor gene phosphatase and tensin homolog (PTEN) in NPC specimens and cell lines, and then we identified PTEN as a direct target of miR-144 in NPC cell lines. PTEN downregulation in miR-144-attenuated cells could increase cell growth, migration and invasion. Mechanistic investigations revealed that miR-144 suppressed the expression of PTEN to increase the expression of pAkt and cyclin D1 to promote G(1)-phase transition and decrease E-cadherin to promote migration and invasion. Taken together, we provide compelling evidence that miR-144 functions as an onco-miRNA in NPC, and its oncoeffects are mediated chiefly by repressing PTEN expression to activate the PI3K/Akt pathway.

Yang H, Hu W, Wang W, et al.
Replanning during intensity modulated radiation therapy improved quality of life in patients with nasopharyngeal carcinoma.
Int J Radiat Oncol Biol Phys. 2013; 85(1):e47-54 [PubMed]

PURPOSE: Anatomic and dosimetric changes have been reported during intensity modulated radiation therapy (IMRT) in patients with nasopharyngeal carcinoma (NPC). The purpose of this study was to evaluate the effects of replanning on quality of life (QoL) and clinical outcomes during the course of IMRT for NPC patients.
METHODS AND MATERIALS: Between June 2007 and August 2011, 129 patients with NPC were enrolled. Forty-three patients received IMRT without replanning, while 86 patients received IMRT replanning after computed tomography (CT) images were retaken part way through therapy. Chinese versions of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 and Head and Neck Quality of Life Questionnaire 35 were completed before treatment began and at the end of treatment and at 1, 3, 6, and 12 months after the completion of treatment. Overall survival (OS) data were compared using the Kaplan-Meier method.
RESULTS: IMRT replanning had a profound impact on the QoL of NPC patients, as determined by statistically significant changes in global QoL and other QoL scales. Additionally, the clinical outcome comparison indicates that replanning during IMRT for NPC significantly improved 2-year local regional control (97.2% vs 92.4%, respectively, P=.040) but did not improve 2-year OS (89.8% vs 82.2%, respectively, P=.475).
CONCLUSIONS: IMRT replanning improves QoL as well as local regional control in patients with NPC. Future research is needed to determine the criteria for replanning for NPC patients undergoing IMRT.

Shao J, Tang J, Ji J, Zhou W
Therapy effects of gold nanorods on the CNE-1 nasopharyngeal carcinoma cell line.
Drug Des Devel Ther. 2012; 6:297-301 [PubMed] Article available free on PMC after 01/02/2014

The use of nanocarriers to deliver drugs to tumor tissue is one of the most important strategies in cancer therapeutics. Recently, gold nanorods (GNRs) have begun to be used in cancer therapy because of their unique properties. The purpose of this study was to show the potential that GNRs have against human nasopharyngeal carcinoma CNE-1 cells, using near-infrared (NIR) laser light. Transmission electron microscopic and ultraviolet-visible spectroscopic investigations confirmed the efficient uptake of the GNRs by CNE-1 and human rhinal epithelia cells. The in vitro NIR photothermal therapy for the CNE-1 and rhinal epithelia cells was designed in three groups: (1) control, (2) laser alone, and (3) GNRs with laser. Fluorescence microscopy images indicated that, at some GNR concentrations and some intensities of NIR laser, GNRs with laser therapy could induce cell death for CNE-1 cells while keeping the rhinal epithelia cells healthy. Therefore, the results of this study suggest that using GNRs with NIR laser therapy can selectively destruct CNE-1 cells while having no effect on normal (rhinal epithelia) cells.

Anghel I, Anghel AG, Dumitru M, Soreanu CC
Nasopharyngeal carcinoma -- analysis of risk factors and immunological markers.
Chirurgia (Bucur). 2012 Sep-Oct; 107(5):640-5 [PubMed]

PURPOSE: To analyze the risk factors associated with Nasopharyngeal Carcinoma (NPC)in patients admitted to the ENT Department at Coltea Clinical Hospital in order to assess the similarities and differences as compared to the epidemiological data internationally reported. Patients and methods: This is a retrospective study on 178 cases that met the inclusion criteria from 2003 to 2011.
RESULTS AND DISCUSSIONS: There are a number of specific characteristics noticed in our study group: a larger number of cases aged over 60 than younger patients; a linear fall in number of the cases aged between 30-39 years; approximately one third of the cases did not have any of the traditional risk factors; more than 10% of the cases were associated with lymphoma, etc. Conclusions: The immunologic pattern of our patients presenting undifferentiated NPC is the following: MNF116, CK19, S100, CD34betaE12, Ki67, EBV positive. The rest of the markers were negative (CerB2, EGFR, COX2, p53, CK7, CD117, VGFR, PCNA, L26/CD20, UHCL1, CD15, CD30, VIM, TTF1, CLA, CK17, CEA, LMP, CD79a, EMA).

Yu HS, Wang X, Song AQ, et al.
Concurrent chemoradiotherapy versus radiotherapy alone for locoregionally advanced nasopharyngeal carcinoma.
Asian Pac J Cancer Prev. 2012; 13(8):3961-5 [PubMed]

OBJECTIVE: To compare the clinical effects of concurrent radiochemotherapy with those of radiotherapy in treating locally advanced nasopharyngeal carcinoma (Stage III~IVa).
METHODS: A total of 95 patients suffering from nasopharyngeal carcinoma (Stage III~IVa) were divided into two groups: concurrent radiochemotherapy (Group CCRT, n=49) and radiotherapy (Group RT, n=46). The two groups were both delivered conventional fractionated radiotherapy, while Group CCRT also received three cycles of PF (DDP+5-Fu) or PLF (DDP+5- Fu+CF) chemotherapy.
RESULTS: The complete remission rate and total remission rate of Group CCRT were higher than those of Group RT (X2=4.72~7.19, P<0.05). The one-year overall survival (OS) rate calculated by the life table method, was also higher than that of Group RT (X2=4.24, P<0.05) as well as the 3-year OS rate, nasopharyngeal control rate and cervical lymph nodes' control rate (X2=4.28~4.40, P<0.05). In addition, the 5-year OS and metastasis-free rates of Group CCRT were higher than those of Group RT and the differences were of statistical importance (X2=3.96~8.26, P<0.05). However, acute toxicity was also obviously higher, the difference in gastrointestinal reactions being statistically significant (X2=11.70, P<0.05).
CONCLUSION: This study demonstrated that concurrent radiochemotherapy could improve the remission rate, overall survival rate and locally control rate. The toxicity of concurrent radiochemotherapy could be tolerated by the patients.